This thesis presents interdisciplinary, collaborative research in the field of synchrotron microbeam radiation therapy (MRT). Synchrotron MRT is an experimental radiotherapy technique under consideration for clinical use, following demonstration of efficacy in tumour-bearing rodent models with remarkable sparing of normal tissue. A high flux, X-ray beam from a synchrotron is segmented into micro-planar arrays of narrow beams, typically 25 μm wide and with peak-to-peak separations of 200 μm. The radiobiological effect of MRT and the underlying cellular mechanisms are poorly understood. The ratio between dose in the ‘peaks’of the microbeams to the dose in the ‘valleys’, between the microbeams, has strong biological significance. However, there are difficulties in accurately measuring the dose distribution for MRT. The aim of this thesis is to address elements of both the dosimetric and radiobiological gaps that exist in the field of synchrotron MRT. A method of film dosimetry and microdensitometry was adapted in order to measure the peak-to-valley dose ratios for synchrotron MRT. Two types of radiochromic film were irradiated in a phantom and also flush against a microbeam collimator on beamline BL28B2 at the SPring-8 synchrotron. The HD-810 and EBT varieties of radiochromic film were used to record peak dose and valley dose respectively. In other experiments, a dose build-up effect was investigated and the half value layer of the beam with and without the microbeam collimator was measured to investigate the effect of the collimator on the beam quality. The valley dose obtained for films placed flush against the collimator was approximately 0.25% of the peak dose. Within the water phantom, the valley dose had increased to between 0.7–1.8% of the peak dose, depending on the depth in the phantom. We also demonstrated, experimentally and by Monte Carlo simulation, that the dose is not maximal on the surface and that there is a dose build-up effect. The microbeam collimator did not make an appreciable difference to the beam quality. The measured values of peak-to-valley dose ratio were higher than those predicted by previously published Monte Carlo simulation papers. For the radiobiological studies, planar (560 Gy) or cross-planar (2 x 280 Gy or 2 x 560 Gy) irradiations were delivered to mice inoculated with mammary tumours in their leg, on beamline BL28B2 at the SPring-8 synchrotron. Immunohistochemical staining for DNA double strand breaks, proliferation and apoptosis was performed on irradiated tissue sections. The MRT response was compared to conventional radiotherapy at 11, 22 or 44 Gy. The results of the study provides the first evidence for a differential tissue response at a cellular level between normal and tumour tissues following synchrotron MRT. Within 24 hours of MRT to tumour, obvious cell migration had occurred into and out of irradiated zones. MRT-irradiated tumours showed significantly less proliferative capacity by 24 hours post-irradiation (P = 0.002). Median survival times for EMT-6.5 and 67NR tumour-bearing mice following MRT (2 x 560 Gy) and conventional radiotherapy (22 Gy) increased significantly compared to unirradiated controls (P < 0.0005). However, there was markedly less normal tissue damage from MRT than from conventional radiotherapy. MRT-treated normal skin mounts a more coordinated repair response than tumours. Cell-cell communication of death signals from directly irradiated, migrating cells, may explain why tumours are less resistant to high dose MRT than normal tissue.

The study evaluated the survival of 364 glioblastoma multiforme (GBM) patients who received different modalities of treatment in two Canadian tertiary care centres. Retrospective and prospective databases were utilized to do a retrospective population based cohort study. The thesis question was among treated GBM patients in Edmonton and Halifax; does the survival rate differ with introduction of concomitant temozolomide and radiation therapy (RT) versus non concomitant treatment? Our results indicate that concomitant temozolomide with radiation therapy and surgery was associated with longer survival in comparison to radiation therapy with surgery. We also found that age; surgical resection and shorter time to radiation therapy are important factors for longer survival. / Clinical epidemiology

The primary goal of this thesis is to improve the precision and efficiency of radiation therapy treatment. This goal is achieved by developing and implementing a direct aperture optimization (DAO) platform where the multileaf collimator (MLC) is rotated between each aperture. The approach is referred to as rotating aperture optimization (RAO). A series of tests is performed to evaluate how a final optimized plan depends on MLC parameters. Imposing constraints on the leaf sequence results in increased efficiency and a simplification of the treatment plan without compromising the quality of the dose distribution. It is also shown that an arrangement of equispaced collimator angles takes full advantage of the flexibility associated with collimator rotation. A study including ten recurring nasopharynx cancer patients is used to evaluate the capabilities of RAO compared to other optimization techniques. It is shown that RAO plans require significantly less linac radiation output (monitor units or MU) while maintaining equivalent dose distribution quality compared to plans generated with the conventional fluence based approach. Furthermore with an improved collimator rotation speed, the RAO plans should be executable in the same or less time than plans generated with the fluence-based approach. For the second part of the study it is shown that plans generated with RAO are as good as or better than plans generated with standard fixed collimator DAO. Film and ion chamber measurements indicate that RAO plans can be delivered more accurately than DAO plans. Additional applications of DAO were investigated through collaboration with two PhD students. First, Monte Carlo was used to generate pencil beam dose distributions for DAO inverse treatment planning (MC-DAO). The MC-DAO technique correctly models traditionally difficult treatment geometries such as small fields and tissue inhomogeneities. The MC-DAO also takes advantage of the improved MU efficiency associated with the DAO technique. Secondly DAO is proposed for adaptive radiation therapy. The results show that plan re-adaptation can be performed more quickly than complete plan regeneration thereby minimizing the time the patient has to spend in the treatment room and reducing the potential for geometric errors in treatment delivery.

Ionizing radiation induces specific proteins involved in DNA repair, cell death, inflammation and tissue injury. The radiation response of proteins within a uniform prostate cancer (PCa) radiotherapy (RT) population has been studied to a limited extent. In this thesis, the proteomic responses of patients undergoing curative RT for intermediate-risk PCa were determined for a panel of pro-inflammatory cytokines from pre-RT baseline to last treatment (39 vs. 33 fractions depending on whether the cohort received primary or post-prostatectomy RT respectively). Longitudinal proteomic research is feasible at our institution based on the study design presented herein. Interferon (IFN)-g and interleukin (IL)-6 were significantly increased during RT and these changes followed consistent patterns modeled by linear and quadratic functions respectively. Furthermore, acute gastrointestinal (GI) and genitourinary (GU) toxicities were significantly associated with IL-2 and IL-1 levels respectively during RT. Taken together this research supports cytokines as potential biomarkers of normal tissue radiation response.

Ionizing radiation induces specific proteins involved in DNA repair, cell death, inflammation and tissue injury. The radiation response of proteins within a uniform prostate cancer (PCa) radiotherapy (RT) population has been studied to a limited extent. In this thesis, the proteomic responses of patients undergoing curative RT for intermediate-risk PCa were determined for a panel of pro-inflammatory cytokines from pre-RT baseline to last treatment (39 vs. 33 fractions depending on whether the cohort received primary or post-prostatectomy RT respectively). Longitudinal proteomic research is feasible at our institution based on the study design presented herein. Interferon (IFN)-g and interleukin (IL)-6 were significantly increased during RT and these changes followed consistent patterns modeled by linear and quadratic functions respectively. Furthermore, acute gastrointestinal (GI) and genitourinary (GU) toxicities were significantly associated with IL-2 and IL-1 levels respectively during RT. Taken together this research supports cytokines as potential biomarkers of normal tissue radiation response.

Abstract In radiation therapy, the beam angles and weightings are usually determined by a treatment planning planner. A uniform dose distribution depends on optimal radiation incident beam angle and individual beam weighting. In this study, simulated annealing with wavelet theory is adopted for solving the optimal beams¡¦ angles and weightings to accomplish a uniform dose distribution inside tumor lesion. Our method can increase the efficiency in solving the optimal angles and weightings in the process of simulated annealing.

Enhanced resistance to radiation could be caused by both chronic hypoxia and acute hypoxic which has been reported in prostate cancer in various studies. Therefore currently used dose prescriptions (70Gy in 35 fractions) for external beam radiation therapy (EBRT) of prostate cancer has been suggested insufficient to provide optimum clinical outcome. In this study, we propose a Biologically Guided Radiation Therapy approach to boost dose in hypoxic prostate tumor regions while sparing the urethra. A previously proposed hypoxia model was modified for prostate cancer and incorporated into treatment plan optimization. The concept of equivalent uniform dose (EUD) was used in the optimization and evaluation of results. CT data from 25 prostate cancer patients who recently received EBRT at the British Columbia Cancer Agency (BCCA) and hypothetical hypoxic regions manually drawn on these CT scans were selected for this study. The results show that our methods could boost dose in target volume to substantially higher levels. EUD of planning target volume increased to more than 80Gy, despite accounting for effects of hypoxia. This increase was achieved with only minor changes in dose in normal tissues, typically less than 5Gy. Notably, urethra sparing was excellent with a EUD around 64Gy. Robustness of the proposed approach is verified against various hypoxic settings. EUD comparison between RT plans in biological guided and conventional approaches using the same RT technique (Volumetric Modulated Arc Therapy) also suggests that biologically guided radiation therapy (BGRT) approach is more suitable for dose painting purposes with the advantage of delivering sufficient dose to hypoxia region in different scenarios and sparing normal tissue better. Furthermore, we also investigated the impact of inter-fraction patient set-up error and intra-fraction organ motion on the high dose gradients achieved with this proposed dose painting method and explored the feasibility of adapting geometrical uncertainties (represented as systematic error and random error) into treatment planning. Image error obtained from EPID images are used to derive systematic uncertainty and random uncertainty. During the geometrical uncertainty adapted optimization, dose matrix in PTV is shifted based on systematic error and convolved with a Gaussian kernel which is pre-calculated using random error. CT sets and organ contours from five patients who enrolled in the previous dose painting i study are selected. For each of them, seven plans are generated using cumulated uncertainty data which was collected after every five fractions. We also present the outcome in terms of equivalent uniform dose (EUD). For four of the patients, EUD history of all seven plans suggests using the proposed optimization method with uncertainty data from the first five fractions, it is possible to achieve the same target coverage of static treatment plans (difference in EUD less than 1Gy). Meanwhile, the elimination of PTV margin also leads to a significant dose reduction (more than 15Gy) in rectum.

The primary goal of this thesis is to improve the precision and efficiency of radiation therapy treatment. This goal is achieved by developing and implementing a direct aperture optimization (DAO) platform where the multileaf collimator (MLC) is rotated between each aperture. The approach is referred to as rotating aperture optimization (RAO). A series of tests is performed to evaluate how a final optimized plan depends on MLC parameters. Imposing constraints on the leaf sequence results in increased efficiency and a simplification of the treatment plan without compromising the quality of the dose distribution. It is also shown that an arrangement of equispaced collimator angles takes full advantage of the flexibility associated with collimator rotation. A study including ten recurring nasopharynx cancer patients is used to evaluate the capabilities of RAO compared to other optimization techniques. It is shown that RAO plans require significantly less linac radiation output (monitor units or MU) while maintaining equivalent dose distribution quality compared to plans generated with the conventional fluence based approach. Furthermore with an improved collimator rotation speed, the RAO plans should be executable in the same or less time than plans generated with the fluence-based approach. For the second part of the study it is shown that plans generated with RAO are as good as or better than plans generated with standard fixed collimator DAO. Film and ion chamber measurements indicate that RAO plans can be delivered more accurately than DAO plans. Additional applications of DAO were investigated through collaboration with two PhD students. First, Monte Carlo was used to generate pencil beam dose distributions for DAO inverse treatment planning (MC-DAO). The MC-DAO technique correctly models traditionally difficult treatment geometries such as small fields and tissue inhomogeneities. The MC-DAO also takes advantage of the improved MU efficiency associated with the DAO technique. Secondly DAO is proposed for adaptive radiation therapy. The results show that plan re-adaptation can be performed more quickly than complete plan regeneration thereby minimizing the time the patient has to spend in the treatment room and reducing the potential for geometric errors in treatment delivery.

No description available.

Enhanced resistance to radiation could be caused by both chronic hypoxia and acute hypoxic which has been reported in prostate cancer in various studies. Therefore currently used dose prescriptions (70Gy in 35 fractions) for external beam radiation therapy (EBRT) of prostate cancer has been suggested insufficient to provide optimum clinical outcome. In this study, we propose a Biologically Guided Radiation Therapy approach to boost dose in hypoxic prostate tumor regions while sparing the urethra. A previously proposed hypoxia model was modified for prostate cancer and incorporated into treatment plan optimization. The concept of equivalent uniform dose (EUD) was used in the optimization and evaluation of results. CT data from 25 prostate cancer patients who recently received EBRT at the British Columbia Cancer Agency (BCCA) and hypothetical hypoxic regions manually drawn on these CT scans were selected for this study. The results show that our methods could boost dose in target volume to substantially higher levels. EUD of planning target volume increased to more than 80Gy, despite accounting for effects of hypoxia. This increase was achieved with only minor changes in dose in normal tissues, typically less than 5Gy. Notably, urethra sparing was excellent with a EUD around 64Gy. Robustness of the proposed approach is verified against various hypoxic settings. EUD comparison between RT plans in biological guided and conventional approaches using the same RT technique (Volumetric Modulated Arc Therapy) also suggests that biologically guided radiation therapy (BGRT) approach is more suitable for dose painting purposes with the advantage of delivering sufficient dose to hypoxia region in different scenarios and sparing normal tissue better. Furthermore, we also investigated the impact of inter-fraction patient set-up error and intra-fraction organ motion on the high dose gradients achieved with this proposed dose painting method and explored the feasibility of adapting geometrical uncertainties (represented as systematic error and random error) into treatment planning. Image error obtained from EPID images are used to derive systematic uncertainty and random uncertainty. During the geometrical uncertainty adapted optimization, dose matrix in PTV is shifted based on systematic error and convolved with a Gaussian kernel which is pre-calculated using random error. CT sets and organ contours from five patients who enrolled in the previous dose painting i study are selected. For each of them, seven plans are generated using cumulated uncertainty data which was collected after every five fractions. We also present the outcome in terms of equivalent uniform dose (EUD). For four of the patients, EUD history of all seven plans suggests using the proposed optimization method with uncertainty data from the first five fractions, it is possible to achieve the same target coverage of static treatment plans (difference in EUD less than 1Gy). Meanwhile, the elimination of PTV margin also leads to a significant dose reduction (more than 15Gy) in rectum.